Various body fluid treatment devices have been developed for purposes of performing treatments by extracorporeal circulation blood purification therapies such as hemodialysis, hemofiltration, plasma separation, plasma fractionation and the like, and those devices having improved safety and performance have been put to practical use.
The body fluid treatment devices are roughly classified into a wet type in which the insides of the hollows of the hollow fiber membranes and the space between the hollow fiber membranes and a container are filled with an aqueous medium, and a non-wet type in which an aqueous medium is not filled. The latter may be further classified into a dry type in which membranes have a water content of only about several percent, and a semi-dry type (also may be referred to as “half-wet type”) in which membranes are moderately wetted with water, a wetting agent or the like. The dry type and semi-dry type body fluid treatment devices have a feature that they have a light product weight and are unlikely to freeze at a low temperature as compared with the wet type body fluid treatment devices. Therefore, the dry type and semi-dry type body fluid treatment devices have a product form particularly excellent in distribution such as transportation and storage.
As a form of packaging these body fluid treatment devices when shipping products, conventionally, body fluid treatment devices are arranged approximately in parallel on a rectangular tray to obtain fixed package intermediates, and the package intermediates are stacked in layers in a rectangular box to obtain a package. The package has been designed paying particular attention to minimizing mechanical damage to the packaged body fluid treatment devices at a time of transportation or falling, and in addition, the package has been designed considering weight reduction, portability, ease of unpacking, and the like.
The body fluid treatment devices are shipped in a sterilized state because they are medical apparatuses. However, if the body fluid treatment devices are packaged after being sterilized one by one, the productivity decreases. Therefore, commonly, the body fluid treatment devices are packaged on one to two dozens basis and thereafter sterilized as a package.
These body fluid treatment devices need to be sterilized completely while being hermetically sealed and packaged before use.
As a method of sterilizing a body fluid treatment device which has been put into practical use, three methods of a gas sterilization method using ethylene oxide gas or the like, an autoclave sterilization method with a high-pressure vapor and a γ-ray irradiation sterilization method have been used mainly. However, in recent years, an electron beam irradiation sterilization method has also become to put into practical use. Of those methods, in regard to the ethylene oxide gas sterilization method, the residual of ethylene oxide gas may cause a problem, which makes it necessary to perform sufficient degassing so as to avoid toxicity. Further, because of prolonged pressurizing and depressurizing a treatment time is repeated, and the performance may be changed depending upon the material. Further, the autoclave sterilization method and the γ-ray irradiation sterilization method have a problem that they are dependent on the properties of the materials constituting a hollow fiber membrane type blood purification device. That is, in the former autoclave sterilization method, the heat resistance in a wet state of a body fluid treatment device is necessary, and depending upon the material, the performance thereof is remarkably degreased during sterilization, which makes it impossible to use the body fluid treatment device. In the latter γ-ray irradiation sterilization method, there are no problems of residual gas and heat resistance, and further, the permeability of an irradiation beam is high. Therefore, the γ-ray irradiation sterilization method is excellent as a method of sterilizing a body fluid treatment device. However, it is well known that a part of a material undergoes a chemical change due to irradiation energy. For example, in a hollow fiber membrane made of a hydrophobic polymer and a hydrophilic polymer constituting a body fluid treatment device, a hydrophilic polymer mainly is denatured and degraded to be eluted from the hollow fiber membrane or to cause a structural change due to cross-linking, and consequently, the transmitting performance, strength, or blood compatibility of the membrane may be decreased.
On the other hand, according to the electron beam irradiation sterilization method, there is no concern of residual toxicity as in the ethylene oxide gas sterilization method, and the sterilization treatment time is not so long as in the autoclave sterilization method, the ethylene oxide gas sterilization method and the γ-ray irradiation sterilization method, and the sterilization treatment may be performed in a short time. Further, when the power is turned off, the irradiation is stopped immediately. When using an accelerator of energy less than 10 MeV, it is not necessary to consider the storage of a radioactive material as in a γ-ray irradiation facility, and in terms of environment the safety is high and a cost is low. Further, a large difference from the γ-ray irradiation lies in that the increase in temperature and the material deterioration of the irradiation object during sterilization are small. Therefore, there is such an advantage as wider selection range of materials, and the further practical use is expected in the future.
However, an electron beam has a smaller permeability to an object compared with a γ-ray, and a transmission distance thereof depends upon the density of the substance to be irradiated. Therefore, conventionally, an electron beam has been practically used only for those which have a relatively uniform shape and are made of a single material, such as surgical gloves and a surgical gown. For example, when an electron beam is irradiated to a body fluid treatment device including a region with a large thickness and a high density, a region where the permeability is insufficient is caused, which increases an absorbed dose distribution (ratio between a maximum absorbed dose and a minimum absorbed dose) between the respective regions in one product. Consequently, problems such as the material deterioration and the eluate may become conspicuous. Specifically, when an irradiation standard is adjusted to the maximum absorbed dose, sterilization at a minimum absorbed dose position becomes insufficient. In contrast, when sterilization is attempted to perform certainly with the irradiation standard being adjusted to the minimum absorbed dose region, the maximum absorbed dose position is irradiated excessively, causing the deterioration and coloring of a material. When the material deterioration such as the decomposition, cross-linking and the like occurs in a hydrophilic polymer, the hydrophilicity of a membrane is impaired, which consequently leads to the decrease in blood compatibility. Thus, depending upon an object to be irradiated, it is not easy to apply an electron beam with small fluctuation in absorbed dose, and there accompanies a problem due to irradiation nonuniformity.
Then, in order to reduce the material deterioration due to the irradiation of an electron beam to an object in a complex shape, study has been conducted mainly from two points of views, that is, in a materials chemistry approach and a process improving approach.
As the materials chemistry approach, a number of technologies of kneading additives such as a radical-trapping agent, an antioxidant and the like into a resin material or allowing the additives to coexist in the vicinity of the resin, which have been widely studied as a method of suppressing the deterioration during irradiation of a radiation including an electron beam. According to these methods, there are advantages in that it is not necessary to modify an irradiation facility substantially, that efficient production may be performed even without prolonging a tact time of irradiation, and the like. However, most of the additives cannot be easily adopted for an extracorporeal circulation type body fluid treatment device in terms of the safety, and particularly regarding a hollow fiber membrane type body fluid treatment device, only a few specific improvement measures against the material deterioration at a time of sterilization with only γ-ray among radiations are found (for example, Patent Documents 1, 2, 7, etc.). Further, only regarding the irradiation of an electron beam, the applicant of the present application has found that the deterioration problem is remarkably solved using a hollow fiber membrane having a specified moisture content and adhesion rate to a radical-trapping material (Patent Document 8). However, although these measures are focused on reducing the material deterioration, there is no viewpoint of reducing the deterioration by decreasing the absorbed dose distribution of an electron beam.
On the other hand, regarding the process improving approach, for example, Patent Document 3 discloses a technology of decreasing an absorbed dose distribution using a shield material together with applying an electron beam under a high accelerated voltage when sterilizing a hollow fiber membrane type dialyzer or an artificial lung with an electron beam. Patent Document 4 discloses an irradiation method comprising an entire irradiation step and a partial shielding step. However, in the former, it is necessary to attach a shield material to an over-irradiated portion for each product individually, and hence, it becomes cumbersome to form a shield having a particular absorbed dose and mount to the product, whereby lowering the operation efficiency. Though the latter has tried to improve the problem, the operation efficiency is still low. Further, Patent Document 5 discloses a technology of, when applying an electron beam to a hollow fiber membrane type body fluid treatment device, applying the electron beam from at least three directions in the case where the body fluid treatment device has a specified product of a density and a thickness. Even in this case, it is necessary to apply an electron beam a number of times while rotating an object to be irradiated, and hence, it is difficult to adopt this technology as a method of sterilizing mass produced products.
On the other hand, Patent Document 6 discloses an irradiation method of applying an electron beam while rotating substances to be irradiated which is arranged in a zigzag arrangement by heaving arrangement pitch intervals during irradiation. This method requires a conveyer transportation mechanism for rotation. Particularly, the mechanism to be set in a transportation conveyer exists immediately under the irradiation beam, and therefore, the mechanism is damaged by a radiation due to continuous irradiation, which makes it substantially difficult to use the mechanism. Further, compared with the irradiation in a package housing a plurality of body fluid treatment devices, the number of body fluid treatment devices that may be irradiated per unit time decreases, and the production efficiency decreases from the viewpoint of commercial production, which increases a cost substantially. Thus, it is difficult to adopt this method.
As described above, from both sides of the process improving approach of uniforming the absorbed dose distribution peculiar to the irradiation of an electron beam, as well as the materials chemistry approach using additives and the like, the study has been conducted to prevent the material deterioration due to the irradiation of an electron beam. However, when considering the perspective of the materials chemistry, only the protection of a material is paid attention to, and a viewpoint of improving by decreasing an absorbed dose distribution of an electron beam is lost. On the other hand, when considering the perspective of uniforming the absorbed dose distribution, only a method of irradiating substances to be irradiated individually and a facility therefore are paid attention to, and a viewpoint of considering an object to be irradiated as a package and treating an object to be irradiated efficiently is lost.
Further, from the viewpoint of safety of medical apparatuses, in the case where substances to be irradiated are individually transported on a conveyer and irradiated, the substances to be irradiated fall from a transportation conveyor or come into contact with a conveyer member dynamically, and a sterilization bag is thus damaged, which causes the risk of increasing the number of viable bacteria before sterilization and of not keeping the completeness of sterilization after sterilization. However, when a package housing a plurality of body fluid treatment devices is irradiated, compared with the case where they are sterilized individually, the above-mentioned risk may be substantially reduced for the reason that the package protects the substances to be irradiated.
More specifically, an approach of considering substances to be irradiated as an aggregate, and, by a simple approach, reducing the irradiation fluctuation of an electron beam efficiently (making an absorbed dose distribution uniform), and reducing the material deterioration, which is neither a microscopic materials chemistry approach nor a large-scale process improving approach, has not been known.    Patent Document 1: JP-B-3076080    Patent Document 2: JP-B-3432240    Patent Document 3: JP-A-H08-275991    Patent Document 4: JP-A-2000-334028    Patent Document 5: JP-A-2000-135274    Patent Document 6: JP-A-2000-325439    Patent Document 7: JP-A-2003-245526    Patent Document 8: WO 2007/018242